Hepatitis C virus (HCV) is a membrane-containing virus belonging to the Flavivirus family. The genome thereof is (+)-RNA (plus-strand RNA), which is 9.6 kb in length and expresses a poly-protein consisting of 3,010 amino acids. The poly-protein is separated into 3 structural proteins and 6 nonstructural proteins by its host cell and viral enzyme.
The 5′ and 3′ termini of the HCV genome have non-translated regions in which base sequences of almost all genotypes are highly conserved. 330-341 nucleotides at the 5′ terminus, and 98 nucleotides downstream of poly A at the 3′ terminus, were recently found, which are thought to play an important role in the RNA replication or translation of the virus. The amino terminus end of the viral genome makes viral structural proteins, a core, E1 and E2, and the remaining region makes nonstructural proteins. The core gene consists of a viral capsid protein, and E1 and E2 consist of viral coat proteins. These proteins are released from each other by a signal peptidase in the endoplasmic reticulum. The nonstructural proteins are processed by serine protease NS3 and cofactor NS4A. NS5B is an enzyme which functions as RNA-dependent RNA polymerase and is most important in the replication of the virus.
Infection with HCV occurs by blood transfusion and community-acquired infection, and there is a report that about 70% of HCV infection is caused by kidney dialysis. It is known that about 20% of HCV infection causes acute hepatitis accompanying liver cirrosis within 5 years and progresses to liver cancer (see Davis et al, New. Engl. J. Med., 321, 1501, 1989; Alter et al, in Current Perspective in Hepatology, p 83, 1989). Such a high chronic infection rate is rare in RNA viruses and shows that HCV is a mediator that causes a high rate of liver cancer. There is still no study on the mechanism of continuous infection with HCV. Recently, HCV infection caused by blood transfusion has been significantly decreased, because HCV tests are sufficiently conducted for all blood, however, community-acquired HCV infection cannot yet be controlled, and thus becomes an important problem worldwide.
In epidemiological terms, HCV is uniformly distributed worldwide, unlike HBV, and it is reported that 1.5-2% of the worldwide population has HCV-infection. HCV infection progresses to chronic hepatitis, and the probability of progression of HCV infection to liver cirrosis and liver cancer is significantly higher than that of infection with hepatitis B virus. Because hepatitis C virus belongs to a completely different viral family, from that of hepatitis B virus in terms of taxonomy, it is impossible to prevent hepatitis C virus with hepatitis B virus vaccine. Also, although there is an attempt to treat hepatitis C virus with α-IFN, a response to α-IFN significantly varies depending on the genotype of hepatitis C virus, and the effect of this treatment method is very insignificant. Particularly, in the case of genotype 1b with which many persons are infected, the therapeutic effect of α-IFN is most insignificant.
Since the RNA genome of HCV was first isolated by cloning in the year 1989, many studies on HCV have been conducted, but an effective therapeutic drug against HCV is not yet developed. As a therapeutic agent against HCV infection, interferon in combination with antiviral drug ribavirin is currently used, but it has an insignificant effect, because it has a low cure rate and shows side effects. Thus, additional compounds for the treatment and prevention of HCV infection have been required.
Accordingly, the present inventors have made efforts to develop compounds having low side effects and toxicity and showing excellent antiviral activity against HCV and, as a result, found that 5,6-dimethylthieno[2,3-d]pyrimidine derivatives represented by Formula 1 below have an excellent inhibitory effect on the proliferation of HCV.